tbuckley/cabot-search huggingface dataset:
Abstract 876: Proximity labeling reveals a role for ADAR and DDX54 in suppressing dsRNA sensing in breast cancer
Authors: Kyle A. Cottrell, Sua Ryu, Luisangely Soto Torres, Angela Schab, Jason D. Weber
Journal: Cancer Research (2022)

Abstract The RNA editing enzyme ADAR has been identified as a therapeutic target for multiple cancers. Through its A-to-I editing activity the p150 isoform of ADAR suppresses activation of dsRNA sensors involved in the innate immune response and translational repression. Recently, our laboratory has shown that p150-ADAR is required for the viability of a subset of triple-negative breast cancer cell lines, thus making p150-ADAR a strong therapeutic target for a disease that lacks targeted therapies. Unlike the p150 isoform, which is interferon inducible, the p110 isoform of ADAR is ubiquitously expressed and has not been shown to suppress dsRNA sensing. To date there is much less known about the role of p110-ADAR in cancer, though it is known to be highly expressed in breast cancer. To begin to explore the role of p110-ADAR in breast cancer, we turned to proximity labeling by APEX2 to identify proteins that may interact with p110-ADAR. Mass-spectrometry of proximity labeled proteins revealed numerous nuclear and nucleolar proteins with roles in multiple aspects of RNA biology, including processing of rRNA and ribosome biogenesis. Among the list of enriched proteins were eight members of the DEAD-box RNA helicase family, including the nucleolar localized DDX54. Co-immunoprecipitation confirmed that p110-ADAR and DDX54 interact, furthermore both localize to nucleoli. Knockdown of DDX54 in non-TNBC cell lines (SK-BR-3 and MCF-7) caused apoptosis and reduced proliferation. Additionally, knockdown of DDX54 caused accumulation of dsRNA within the nucleolus and activation of the dsRNA sensor PKR. Knockdown of ADAR, which alone did not affect proliferation or phosphorylation of PKR in the above cell lines, synergized with DDX54 knockdown to cause increased cell death and further activation of PKR. ADAR knockdown did not synergize with knockdown of another ADAR-interacting DEAD-box helicase, DDX17, suggesting that the observed phenotype is not common to combined knockdown of ADAR and any RNA helicase. These findings suggest that combined inhibition/depletion of ADAR and DDX54 may serve as therapeutic strategy for breast tumors, including those that are refractory to ADAR inhibition/depletion alone. Citation Format: Kyle A. Cottrell, Sua Ryu, Luisangely Soto Torres, Angela Schab, Jason D. Weber. Proximity labeling reveals a role for ADAR and DDX54 in suppressing dsRNA sensing in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 876.
Highlighting uncertainty in clinical risk prediction using a model of emergency laparotomy mortality risk
Authors: Jakob F. Mathiszig-Lee, Finneas J. R. Catling, S. Ramani Moonesinghe, Stephen J. Brett
Journal: npj Digital Medicine (2022)

Abstract Clinical prediction models typically make point estimates of risk. However, values of key variables are often missing during model development or at prediction time, meaning that the point estimates mask significant uncertainty and can lead to over-confident decision making. We present a model of mortality risk in emergency laparotomy which instead presents a distribution of predicted risks, highlighting the uncertainty over the risk of death with an intuitive visualisation. We developed and validated our model using data from 127134 emergency laparotomies from patients in England and Wales during 2013–2019. We captured the uncertainty arising from missing data using multiple imputation, allowing prospective, patient-specific imputation for variables that were frequently missing. Prospective imputation allows early prognostication in patients where these variables are not yet measured, accounting for the additional uncertainty this induces. Our model showed good discrimination and calibration (95% confidence intervals: Brier score 0.071–0.078, C statistic 0.859–0.873, calibration error 0.031–0.059) on unseen data from 37 hospitals, consistently improving upon the current gold-standard model. The dispersion of the predicted risks varied significantly between patients and increased where prospective imputation occurred. We present a case study that illustrates the potential impact of uncertainty quantification on clinical decision making. Our model improves mortality risk prediction in emergency laparotomy and has the potential to inform decision-makers and assist discussions with patients and their families. Our analysis code was robustly developed and is publicly available for easy replication of our study and adaptation to predicting other outcomes.
Abstract 3526: Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis
Authors: Ibis R. Vera-Urbina, Estefania Ayala, Ediel Rodriguez, Hilmaris Centeno-Girona, Leslie Casiano, Belisa Suarez, Marcia Cruz-Correa, Maria Gonzalez-Pons
Journal: Cancer Research (2022)

Abstract Introduction: Colorectal cancer (CRC) is the 1st and 2nd leading cause of cancer death in men and women in Puerto Rico and the U.S., respectively. A dynamic balance between the host immune system and the gut bacterial communities is essential to protect colonic tissues against chronic inflammation, which may lead to CRC. The main goal of this study was to investigate if SNPs in the promoter regions of the IL-1β, IL-6 and IL-10, key cytokines that regulate gut inflammation, increase the risk for colorectal adenomas by enriching a subset of the toxin-producing gut microbiota (gene-environment interaction). Methods: Using a case-control study design, associations between having pro-inflammatory SNPs and/or bacterial toxins in colonic mucosa or stool were assessed using odds ratios. TaqMan® SNP Genotyping Assays (ThermoFisher Scientific) for IL- 1β (rs1143627), IL-6 (rs1800795), and IL-10 (rs1800871) were performed according to the manufacturer’s recommendations. The presence of bacterial toxin genes (pks, TcPC, GelE, cnf-1, CDT, murB, and usp) in stool were determined using the QuantiTect SYBR Green PCR kit (QIAGEN). Results: Our preliminary analyses showed that individuals with the IL-1β pro-inflammatory genotype were 1.5-times more likely to have colorectal adenomas (n=232; p=0.1). Detection of usp or pks in stool (n=147) was positively associated with having adenomas (OR=2.95; CI 95%= 0.92-9.45 and OR=2.91; CI 95%=0.58-14.50, respectively). Conclusion: An evaluation of the association between having pro-inflammatory genotypes, the presence of bacterial toxin genes in stool, and colorectal adenomas using a larger sample size is warranted and currently underway. The integration of modifiable (e.g. gut bacterial toxins) and non-modifiable (e.g. host genetics) risk factors in a stratified model for CRC risk stratification and/or prevention may enhance current screening approaches. Citation Format: Ibis R. Vera-Urbina, Estefania Ayala, Ediel Rodriguez, Hilmaris Centeno-Girona, Leslie Casiano, Belisa Suarez, Marcia Cruz-Correa, Maria Gonzalez-Pons. Host genetic susceptibility to gut microbiota-driven colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3526.
Abstract 5958: CD276/CD47-targeted antibody-drug conjugates to treat triple-negative breast cancers
Authors: Yingnan Si, Kai Chen, Seulhee Kim, Zhuoxin Zhou, Lufang Zhou, X. Margaret Liu
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancers (TNBCs) are highly aggressive, heterologous and frequently recurrent. The standard radiotherapy and chemotherapy have limited clinical benefits while the combined therapies or antibody-drug conjugates (ADCs) are promising to treat TNBC. The objective of this study was to develop a combined therapy, CD276/CD47-targeted ADCs, for TNBC treatment. Specifically, the CD276 and CD47 surface receptors were identified with immunohistochemistry staining of drug-sensitive and resistant patient tissues and confirmed in other assays. Two innovative monoclonal antibodies (mAbs), i.e. anti-CD276 mAb and anti-CD47 mAb that target the N-glycosylated extracellular domains (Leu29-Pro245 and Gln19-Glu141) of surface receptors, were developed using hybridoma technology. The top mAb clones with high surface binding, drug delivery and affinity were screened, produced in fed-batch culture, purified using liquid chromatography, and conjugated with payload mertansine (DM1). Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the CD276/CD47 ADCs effectively target human and mouse TNBC cells and xenograft models. The in vitro anti-cancer cytotoxicity was confirmed in multiple cell lines (MDA-MB-468, MDA-MB-231, 4T1), and in vivo evaluations using TNBC cell line-derived xenograft models and patient-derived xenograft (PDX) models demonstrated high anti-tumor efficacy and tumoral immunity of the dually targeted ADCs. In addition, whole blood analysis indicated that neither CD276 mAb nor CD47 mAb showed general immune toxicity in immunocompetent model. The maximal tolerated dose (MTD), pharmacokinetics (PK) and biodistribution will be further investigated. This study indicated that the ADCs dually targeting CD276 and CD47 have great potential to treat TNBCs. Citation Format: Yingnan Si, Kai Chen, Seulhee Kim, Zhuoxin Zhou, Lufang Zhou, X. Margaret Liu. CD276/CD47-targeted antibody-drug conjugates to treat triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5958.
Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer
Authors: Zhenghang Wang, Qi Zhang, Changsong Qi, Yuezong Bai, Feilong Zhao, Hui Chen, Zhongwu Li, Xicheng Wang, Mifen Chen, Jifang Gong, Zhi Peng, Xiaotian Zhang, Jinping Cai, Shiqing Chen, Xiaochen Zhao, Lin Shen, Jian Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Gastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer. Methods Three independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data. Results AKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (mutant AKT1 or CDH1) GI cancer had significantly shorter PFS (HR=8.36, p&lt;0.001) and overall survival (OS, HR=5.17, p&lt;0.001) than IOpred-WT (wild-type for both AKT1 and CDH1) cases upon ICI treatment. The validation cohort also confirmed the correlation between IOpred-mutation and poorer prognosis (PFS, HR=4.68, p=0.004; OS, HR=15.98, p&lt;0.001) in dMMR/MSI-H patients after ICIs. The PPV of IOpred in identifying primary resistance to ICIs was 80% (4/5) in the validation cohort. Additionally, IOpred-WT patients could be further stratified by tumor mutational burden (TMB), wherein TMB-low patients (TMB ≤26.19 mutations per megabase (Mb)) had a significantly higher primary resistance rate to ICIs (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients (TMB &gt;26.19 mutations/Mb). Conclusions IOpred was identified as a powerful predictor of primary resistance to ICIs in dMMR/MSI-H GI cancer, which might serve as a promising biomarker to help guide immunotherapy decision-making.
Abstract 5416: RNA-seq and proteomics to identify response to immunotherapy in advanced melanoma: a Spanish Melanoma Group Study
Authors: Lucia Trilla-Fuertes, Guillermo Prado-Vazquez, Angelo Gámez-Pozo, Rocio Lopez-Vacas, Maria Isabel Lumbreras Herrera, Virtudes Soriano, Fernando Garicano, Maria Jose Lecumberri, Maria Rodriguez, Margarita Majem, Elisabeth Perez, Maria Gonzalez-Cao, Juana Oramas, Alejandra Magdaleno, Joaquin Fra, Alfonso Martin, Monica Corral, Teresa Puertolas, Juan Angel Fresno Vara, Enrique Espinosa
Journal: Cancer Research (2022)

Abstract Background: Prediction of response to immunotherapy remains an unmet need in the field of advanced melanoma. Methods: Computational analyses, including probabilistic graphical models, sparse k-means, and consensus cluster, were used to characterize melanoma TCGA samples. The implication of the identified processes in response to immunotherapy was then studied in an independent cohort of 53 patients with advanced melanoma and treated with PD-1 inhibitors. Paraffin samples from this cohort were analyzed using RNA-seq and mass-spectrometry proteomics. Results: In the TCGA cohort, there were two different layers of information: one related to molecular features of the tumor (based on keratinization, melanogenesis, and extracellular space), and one related to immune status. Therefore, two independent classifications of TCGA melanoma samples were established: molecular and immune. The immune classification distinguished between responders and not responders to immunotherapy in the second cohort (p= 0.0006, HR=6.52). Finally, high-throughput proteomics was used to characterize molecular mechanisms involved in response to immunotherapy, identifying several biological processes and proteins that may be relevant in treatment selection for patients who do not respond. Conclusions: We established that the immune information was independent of tumor molecular features in melanomas included in the TCGA. An immune classification of these tumors was established. This immune classification predicted response to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors. Finally, proteomics was used to identify possible targets in those patients who did not respond to immunotherapy. Citation Format: Lucia Trilla-Fuertes, Guillermo Prado-Vazquez, Angelo Gámez-Pozo, Rocio Lopez-Vacas, Maria Isabel Lumbreras Herrera, Virtudes Soriano, Fernando Garicano, Maria Jose Lecumberri, Maria Rodriguez, Margarita Majem, Elisabeth Perez, Maria Gonzalez-Cao, Juana Oramas, Alejandra Magdaleno, Joaquin Fra, Alfonso Martin, Monica Corral, Teresa Puertolas, Juan Angel Fresno Vara, Enrique Espinosa. RNA-seq and proteomics to identify response to immunotherapy in advanced melanoma: a Spanish Melanoma Group Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5416.
Abstract 5231: Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel <i>ARL1-MET</i> fusion
Authors: Qing Ma, Lingping Kong, Diansheng Zhong
Journal: Cancer Research (2022)

Abstract Background: With the use of high-resolution chest imaging system, an increasing number of lung cancer patients are being diagnosed with multiple primary lung cancer (MPLC). Although surgery is considered as the first choice of treatment for early MPLC, targeted therapy is essential in the management of unresectable MPLC. To date, the driver oncogenes reported in the patients with MPLC are limited, and MET fusion has not yet been reported in MPLC. Case presentation: In this case, we reported a female patient with simultaneous MPLC (sMPLC). A novel ARL1-MET fusion was detected in her right lung tumor tissues using next-generation sequencing (NGS). The patient achieved about 5-month progressive-free survival (PFS) after receiving Crizotinib for the unresectable right lung malignancies. Conclusion: To the best of our knowledge, this case provided the first clinical evidence that the novel ARL1-MET fusion might be an actionable mutation in sMPLC. Citation Format: Qing Ma, Lingping Kong, Diansheng Zhong. Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel ARL1-MET fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5231.
Abstract 2937: Mutational analysis of ORF-8 of SARS-CoV-2 - a window to immunotherapy
Authors: Gopika Trieu, Nikita Mehta, Jeffrey Park, Andrew Ionescu, Lily Asgari, Vuong Trieu
Journal: Cancer Research (2022)

Abstract Background: TGF-Beta plays an important role in immune evasion in oncology. Similarly, SARS-Cov-2, the causal agent of the COVID-19 pandemic, also has an immune evasion function. This is mediated by ORF-8 through its interaction with multiple immune regulatory elements, including TGF-beta. This is a mutational analysis of ORF-8. Methods: We took advantage of the database of millions of SARS-CoV-2 genomes are archived and organized in phylogenetic relationships to show the evolution of ORF-8. Site numbering and genome structure use Wuhan-Hu-1/2019 as reference. The phylogeny is rooted relative to early samples from Wuhan. Temporal resolution assumes a nucleotide substitution rate of 8 × 10^-4 subs per site per year. ( https://nextstrain.org/). The epidemiological data provided at https://ourworldindata.org/coronavirus was used to determine the property of the variants using mortality and infectivity data at the site. Results: Scan of ORF-8 revealed a high rate of mutation at aa119 and aa120. More importantly, the mutation at 120 or 119 that resulted in null ORF8 clearly delineates the pre-Delta and Delta SARS-Cov-2. In fact, all the delta lineages exhibited the null mutation at 119/120. This region is important for the dimerization of ORF-8 and possibly its interaction with host TGF-beta. All other variants, including the alpha variants, are wild type (aa120 = F). Monitoring the mutations over the last several months indicated that the delta variants have now picked up the wild type F at aa120 (Faa120) in Egypt or the L at aa 120 (Laa120) in India. The epidemiology of Egypt and India indicates that the Faa120 is more immune evasive and suggestive that more infectious but not more lethal. Conclusions: This is an opportunity to monitor in real-time the evolution of ORF-8 and how it is interacting with the host immune system. Additionally, since our current clinical trial on TGF-beta inhibitors is in India and Latin America, it is an opportunity to correlate clinical findings to molecular and epidemiological data for these variants. If we are correct, the Faa120 will emerge as the dominant variant in the next wave of COVID-19. Citation Format: Gopika Trieu, Nikita Mehta, Jeffrey Park, Andrew Ionescu, Lily Asgari, Vuong Trieu. Mutational analysis of ORF-8 of SARS-CoV-2 - a window to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2937.
CD147 a direct target of miR-146a supports energy metabolism and promotes tumor growth in ALK+ ALCL
Authors: Ivonne-Aidee Montes-Mojarro, Julia Steinhilber, Christoph M. Griessinger, Achim Rau, Ann-Kathrin Gersmann, Ursula Kohlhofer, Petra Fallier-Becker, Huan-Chang Liang, Ute Hofmann, Mathias Haag, Wolfram Klapper, Elke Schaeffeler, Bernd J. Pichler, Matthias Schwab, Falko Fend, Irina Bonzheim, Leticia Quintanilla-Martinez
Journal: Leukemia (2022)

Abstract We recently reported that miR-146a is differentially expressed in ALK+ and ALK− anaplastic large cell lymphoma (ALCL). In this study, the downstream targets of miR-146a in ALK+ ALCL were investigated by transcriptome analysis, identifying CD147 as potential target gene. Because CD147 is differentially expressed in ALK+ ALCL versus ALK− ALCL and normal T cells, this gene emerged as a strong candidate for the pathogenesis of this tumor. Here we demonstrate that CD147 is a direct target of miR-146 and contributes to the survival and proliferation of ALK+ ALCL cells in vitro and to the engraftment and tumor growth in vivo in an ALK+ ALCL-xenotransplant mouse model. CD147 knockdown in ALK+ ALCL cells resulted in loss of monocarboxylate transporter 1 (MCT1) expression, reduced glucose consumption and tumor growth retardation, as demonstrated by [ 18 F]FDG-PET/MRI analysis. Investigation of metabolism in vitro and in vivo supported these findings, revealing reduced aerobic glycolysis and increased basal respiration in CD147 knockdown. In conclusion, our findings indicate that CD147 is of vital importance for ALK+ ALCL to maintain the high energy demand of rapid cell proliferation, promoting lactate export, and tumor growth. Furthermore, CD147 has the potential to serve as a novel therapeutic target in ALK+ ALCL, and warrants further investigation.
Abstract 4161: An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity
Authors: Xuedan He
Journal: Cancer Research (2022)

Abstract Tumor-associated self-antigens are cancer vaccines targets but suffer from limited immunogenicity. There have been examples of mutated, short self-peptides inducing epitope-specific CD8+ T cells more efficiently than the wild-type epitope, but current approaches cannot yet reliably generate such enhanced mimotopes (“e-mimotopes”). Here, we present a generalized strategy to develop e-mimotopes, using the tyrosinase-related protein 2 peptide Trp2180-188, a major histocompatibility complex (MHC)-I epitope, as a test case. Using a vaccine adjuvant that induces peptide particle formation and strong cellular responses with nanogram antigen doses, a two-step method systematically identified e-mimotope candidates with murine immunization. First, position-scanning peptide micro libraries were generated in which each position of the wild-type epitope sequence was randomized. Randomization of only one specific residue of the Trp2 epitope increased anti-tumor immunogenicity. Second, all 20 amino acids were individually substituted and tested at that position, enabling the identification of two e-mimotopes with single amino acid mutations. Despite similar MHC-I affinity compared to the wild-type epitope, e-mimotope immunization elicited improved Trp2-specific cytotoxic T cell phenotypes and improved T cell receptor affinity for both the e-mimotopes and the native epitope, resulting in better outcomes in multiple prophylactic and therapeutic tumor models. The screening method was also applied to other targets with different murine MHC-I restriction elements, including the gp70 AH1 epitope, to identify additional e-mimotopes with enhanced potency. Citation Format: Xuedan He. An in vivo screen to identify short peptide mimotopes with enhanced anti-tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4161.